Unlike other resident neural cells that are of neuroectodermal origin, microglia are resident neural cells of mesodermal origin. Traditionally recognized for their immune functions during disease, new roles are being attributed to these cells in the development and maintenance of the central nervous system (CNS) including specific communication with neurons. In this review, we highlight some of the recent findings on the bidirectional interaction between neurons and microglia. We discuss these interactions along two lines. First, we review data that suggest that microglial activity is modulated by neuronal signals, focusing on evidence that (i) neurons are capable of regulating microglial activation state and influence basal microglial activities; (ii) classic neurotransmitters affect microglial behavior; (iii) chemotactic signals attract microglia during acute neuronal injury. Next, we discuss some of the recent data on how microglia signal to neurons. Signaling mechanisms include (i) direct physical contact of microglial processes with neuronal elements; (ii) microglial regulation of neuronal synapse and circuit by fractalkine, complement, and DAP12 signaling. In addition, we discuss the use of microglial depletion strategies in studying the role of microglia in neuronal development and synaptic physiology. Deciphering the mechanisms of bidirectional microglial-neuronal communication provides novel insights in understanding microglial function in both the healthy and diseased brain. 1. Introduction Microglia comprise a unique subset of glial cells as the resident macrophages of the central nervous system (CNS). Although their developmental origin has been debated for several decades, the general contemporary consensus is that microglia originate from two sources to populate the CNS: an early source in the embryonic yolk sac and a later source from myeloid progenitors that invade the CNS during embryonic and postnatal development. Subsequent to this early colonization, the resident microglial population remains stable and is maintained through adulthood [1–3]. Traditionally, microglia were studied for their role as pathologically responsive cells with virtually no interest in their functions in the healthy brain. However, given their presence in various species from the invertebrate leech to advanced mammals, as well as their emergence during early development, their functions cannot simply be restricted to pathological settings [4]. The last decade has witnessed a dramatic increase in microglia studies in the healthy brain. These studies suggest an
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